Abnormalities in the plasminogen activator (PA) pathways have been implicated in the pathogenesis of acute lung (ALl) and pleural injury. Recent interventional trials suggest that targeting these pathways can reduce mortality in sepsis and protect against acute lung or pleural injury. The Project Leaders of this PPG have developed evidence that these pathways can influence ALl and pleural injury through newly recognized mechanisms. However the pathogenic mechanisms that link the PA pathways to ALl and pleural injury are poody understood and are likely to involve non-proteolytic signal-transducing pathways. Our thematic objective is to address this gap by defining novel mechanisms by which urokinase (uPA), its receptor (uPAR), other novel uPA receptors, its inhibitor PAl-l, and plasmin influence the course of inflammation, remodeling of transitional matrix and accelerated fibrosis in ALl and pleural injury. In Proiect 1, expression of PAl-1 and uPAR by the mesothelium will be studied with a focus on posttranscriptional regulation and a mechanistically based intervention to prevent pleural Ioculation will be further evaluated. Project 2 will elucidate novel posttranscriptional mechanisms by which uPA and uPAR are regulated by the lung epithelium. Proiect 3 will define novel pathways by which uPA regulates pulmonary vasoconstriction and lung edema after ALl and the role of defensin in the process. Proiect 4 will elucidate novel mechanisms by which plasmin may influence remodeling during evolving ALl or pleural injury. These interactive projects derive from active programs directed by experienced Project Leaders and are now oriented to our thematic objective. In vitro, in vivo and interventional methods will be used. Based on reported recent clinical and preclinical trials, this PPG will accelerate the acquisition of new, clinically relevant information that will hasten the development of better treatments for ALl and/or pleural injury.